Transcriptomics,Genomics

Dataset Information

41

Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance


ABSTRACT: Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g. via bioreactor systems, through which culture medium is constantly pumped at a flow rate reflecting physiological conditions. Here, we show that both Staticic 3D growth and 3D growth within a bioreactor system modulate key hallmarks of cancer cells, including proliferation and cell death as well as macroautophagy, a recycling pathway often activated by highly proliferative tumors to cope with metabolic stress. The autophagy-related gene expression profiles of 2D- and 3D-grown cells are substantially different, with the 3D-grown cells exhibiting an expression profile closely resembling the (patho-) physiological Statice of a tumor. Underscoring the importance of this pathway, autophagy-controlling transcription factors, such as TFEB and FOXO3, are upregulated in tumors, and 3D-grown cells have increased expression compared with cells grown in 2D conditions. Three-dimensional cultures depleted of the autophagy mediators BECN1, ATG5 or ATG7 or the transcription factor FOXO3, are more sensitive to cytotoxic treatment. Accordingly, combining cytotoxic treatment with compounds affecting late autophagic flux, such as chloroquine, renders the 3D-grown cells more susceptible to therapy and increases intracellular doxorubicin concentration to the level of 2D-grown cells. Altogether, 3D cultures are a valuable tool to study drug response of tumor cells, as these models recapitulate (patho-) physiologically relevant pathways, such as autophagy. Overall design: Total RNA was isolated from neuroblastoma cell (BE(2)-C) cultures grown under 2D, 3D-Staticic and 3D-bioreactor conditions from three independent experiments and human neuroblastoma tissue samples chosen to resemble characteristics of BE(2)-C cells (each in triplicate)

INSTRUMENT(S): Illumina HumanHT-12 V4.0 expression beadchip

SUBMITTER: Emily Koeneke  

PROVIDER: GSE100020 | GEO | 2017-07-04

SECONDARY ACCESSION(S): PRJNA390494

REPOSITORIES: GEO

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Publications

Three-dimensional tumor cell growth stimulates autophagic flux and recapitulates chemotherapy resistance.

Bingel Corinna C   Koeneke Emily E   Ridinger Johannes J   Bittmann Annika A   Sill Martin M   Peterziel Heike H   Wrobel Jagoda K JK   Rettig Inga I   Milde Till T   Fernekorn Uta U   Weise Frank F   Schober Andreas A   Witt Olaf O   Oehme Ina I  

Cell Death & Disease 20170824 8


Current preclinical models in tumor biology are limited in their ability to recapitulate relevant (patho-) physiological processes, including autophagy. Three-dimensional (3D) growth cultures have frequently been proposed to overcome the lack of correlation between two-dimensional (2D) monolayer cell cultures and human tumors in preclinical drug testing. Besides 3D growth, it is also advantageous to simulate shear stress, compound flux and removal of metabolites, e.g., via bioreactor systems, th  ...[more]

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